It is proposed to continue to operate and to extend the capabilities of the Rockefeller University Biotechnology Research Resource. Emphasis will be placed upon the mass spectrometry of high molecular mass biomolecules. A new focus of the Resource will involve the use of tandem mass spectrometry (MS-MS) as an analytical tool for the detailed structural analysis of biomolecules. Two separate approaches to tandem MS will be followed involving (i) the acquisition and application of a commercial triple- quadrupole mass spectrometer using electrospray ionization and liquid secondary ionization MS, and (ii) the assembly and development of an ultra- high sensitivity matrix-assisted laser desorption time-of-flight-ion trap tandem mass spectrometer. The major subdivisions of the Resource activity will be basic research in mass spectrometry, collaborative research on biomedical problems, and analytical service work. The basic research activities will involve investigations of the physical and chemical phenomena involved in matrix-assisted laser desorption MS and electrospray ionization MS and further improvements to the instrumentation, techniques, and applications of these two powerful new methods. The goal of this work is to measure routinely the molecular mass of any peptide or protein at subpicomole levels. Other basic research will focus on the development of ultra sensitive methods for determining the primary structures of biomolecules. Collaborative projects will involve studies (1) of the contribution of human variation at the apolipoprotein gene loci to atherosclerosis susceptibility (J. Breslow, Rockefeller); (2) towards an understanding of the etiology and pathobiology of scrapie and its related neurological disorders (S. Prusiner, UCSF); (3) towards the development of animal models for Alzheimer's disease (J. Buxbaum, P. Greengard, Rockefeller); (4) to improve the chemistry of peptide synthesis (B. Merrifield, Rockefeller); (5) of the structures of mating pheromones from ciliated protozoa (R.A. Bradshaw, U.C. Irvine); (6) of the chemical structure of cross-linked hemoglobin as a potential blood substitute (J. Manning, Rockefeller); (7) of the structure-function relations of gonadotropins and their role in human reproduction (S. Birken, R. Canfield, Columbia); (8) on the definition of posttranslational modifications of nuclear transcription factors (N. Heintz, Rockefeller); (9) of the structure of bacterial cell wall glycopeptides (A. Tomasz, Rockefeller); (10) of posttranslational modifications in the G-protein ?-subunit (P. Backlund, NIMH); (11) of posttranslational modifications in the anaphylatoxins from human serum (T. Hugli, Scripps); (12) of signal transduction mechanisms focussing on guanine nucleotide-binding regulatory proteins (A. Gilman, U.T. Southwestern Medical Center), amongst others.